Influence of the HMG-CoA-reductase inhibitor lovastatin on cholesterol saturation index and nucleation time of duodenal bile

Owing to the presence of hyperlipoproteinemia IIa, twelve patients without gallstones were treated daily with 20 mg, 40 mg and 80 mg of Lovastatin, each dose being administered for 4 weeks. At the conclusion of each 4-week treatment phase, bile was obtained from the fasting patient following injection of 5 micrograms ceruletid i.v. with the aid of a duodenal tube. The long nucleation time of bile was not shortened by the therapy. The bile cholesterol saturation index showed a decline with Lovastatin, which was particularly obvious in patients with an initially oversaturated bile. In contrast to other lipid-reducing agents (e.g. fibrates), Lovastatin does not lead to increased lithogenesis of the bile, but may in certain circumstances have an prophylactic effect against the formation of gallstones.     

Tumor location and nature of lymphatic vessels are key determinants of cancer metastasis

Tumor metastasis to lymph nodes is a key indicator of patient survival, and is enhanced by the neo-lymphatics induced by tumor-secreted VEGF-C or VEGF-D, acting via VEGFR-3 signalling. These targets constitute important avenues for anti-metastatic treatment. Despite this new understanding, clinical observations linking metastasis with tumor depth or location suggest that lymphangiogenic growth factors are not the sole determinants of metastasis. Here we explored the influence of tumor proximity to lymphatics capable of responding to growth factors on nodal metastasis in a murine VEGF-D over-expression tumor model. We found that primary tumor location profoundly influenced VEGF-D-mediated lymph node metastasis: 89 % of tumors associated with the flank skin metastasised, in contrast with only 19 % of tumors located more deeply on the body wall (p < 0.01). Lymphatics in metastatic tumors arose from small lymphatics, and displayed distinct molecular and morphological profiles compared with those found in normal lymphatics. Smaller lymphatic subtypes were more abundant in skin (2.5-fold, p < 0.01) than in body wall, providing a richer source of lymphatics for VEGF-D⁺ skin tumors, a phenomenon also confirmed in human samples. This study shows that the proximity of a VEGF-D⁺ primary tumor to small lymphatics is an important determinant of metastasis. These observations may explain why tumor location relative to the lymphatic network is prognostically important for some human cancers.     

The Production and Characterization of Novel Heavy-Chain Antibodies Against the Tandem Repeat Region of MUC1 Mucin

Camelidae are known to produce immunoglobulins (Igs) devoid of light chains and constant heavy-chain domains (CH₁). Antigen-specific fragments of these heavy-chain IgGs (VHH) are of great interest in biotechnology applications. This paper describes the first example of successfully raised heavy-chain antibodies in Camelus dromedarius (single-humped camel) and Camelus bactrianus (two-humped camel) against a MUC1 related peptide that is found to be an important epitope expressed in cancerous tissue. Camels were immunized against a synthetic peptide corresponding to the tandem repeat region of MUC1 mucin and cancerous tissue preparation obtained from patients suffering from breast carcinoma. Three IgG subclasses with different binding properties to protein A and G were purified by affinity chromatography. Both conventional and heavy-chain IgG antibodies were produced in response to MUC1-related peptide. The elicited antibodies could react specifically with the tandem repeat region of MUC1 mucin in an enzyme linked immunosorbant assay (ELISA). Anti-peptide antibodies were purified after passing antiserum over two affinity chromatography columns. Using ELISA, immunocytochemistry and Western blotting, the interaction of purified antibodies with different antigens was evaluated. The antibodies were observed to be selectively bound to antigens namely: MUC1 peptide (tandem repeat region), human milk fat globule membrane (HMFG), deglycosylated human milk fat globule membrane (D-HMFG), homogenized cancerous breast tissue and a native MUC1 purified from ascitic fluid. K_a values of specific polyclonal anti-peptide antibodies were estimated in C. dromedarius and C. bactrianus, as 7 × 10¹⁰ M^{? 1} and 1.4 × 10¹⁰ M^{? 1} respectively.     

Progressive-toric IOL design reduces residual astigmatism with increasing pupil size: a ray-tracing simulation based on corneal topography data

Population studies indicate that astigmatism decreases from the corneal center toward the periphery. A standard toric intraocular lens (IOL) with a constant cylinder power cannot correct uniformly across this gradient. We built an astigmatic eye model based on corneal topography data. A progressive-toric lens with gradually decreasing cylinder power was compared with an identically designed lens but featuring conventional astigmatism correction. Residual astigmatism did not differ significantly (P=0.06) at 3 mm, and the Strehl ratio was identical for both lenses (0.51 ±0.15, P=0.88). At 5 mm, the progressive IOL yielded significantly lower residual astigmatism by 0.10 D (P<0.001). The Strehl ratio was 0.30 ±0.08 with the progressive and 0.29 ±0.08 with the standard lens (P<0.001). At 3 mm, the optical performance was comparable for both IOLs. However, at 5 mm, the progressive-toric was more effective in correcting astigmatism, and it yielded reduced residual astigmatism compared to a standard toric lens.     

Ebola Policies That Hinder Epidemic Response by Limiting Scientific Discourse

There is an unprecedented epidemic of Ebola virus disease (EVD) in west Africa. There has been a strong response from dedicated health professionals. However, there have also been irrational and fear-based responses that have contributed to misallocation of resources, stigma, and deincentivizing volunteers to combat Ebola at its source. Recently, the State of Louisiana Department of Health and Hospitals issued a ban on those coming from affected countries wishing to attend the annual meetings of American Society of Tropical Medicine and Hygiene and the American Public Health Association, both of which were held in New Orleans. We argue against such policies, question evidence and motivations, and discuss their practical and ethical implications in hampering effective responses to EVD by the scientific community. We aim to shed light on this issue and its implications for the future of public health interventions, reflect on the responsibility of health providers and professional societies as advocates for patients and the public health, and call for health professionals and societies to work to challenge inappropriate political responses to public health crises.On October 28, 2014, 5 days before the annual meeting of the American Society of Tropical Medicine and Hygiene (ASTMH) in New Orleans, the Louisiana Department of Health and Hospitals (DOHH) in conjunction with the Governor''s Office for Homeland Security and Emergency Preparedness announced to all ASTMH attendees that “individuals who traveled to and returned from the countries of Sierra Leone, Liberia or Guinea in the past 21 days, or have had contact with a known EVD [Ebola virus disease] patient in that time period, should NOT travel to New Orleans to attend the conference. Given that conference participants with a travel and exposure history for EVD are recommended not to participate in large group settings (such as this conference) or to utilize public transport, we see no utility in you traveling to New Orleans to simply be confined to your room.” Furthermore, the letter stated that “from a medical perspective, asymptomatic individuals are not at risk of exposing others; however, the State is committed to preventing any unnecessary exposure of Ebola to the general public. In Louisiana, we love to welcome visitors, but we must balance that hospitality with the protection of Louisiana residents and other visitors.”¹While acknowledging recommendations of the Centers for Disease Control and Prevention (CDC) that asymptomatic individuals are not a risk to others, the statement went beyond the CDC guidelines and implied a potential threat from conference attendees, even those without exposure to EVD, based solely on travel history to countries affected by the epidemic. We believe the DOHH should appreciate the negative ramifications of unscientifically based travel bans and quarantine policies and rather, follow evidence-based guidelines to protect the public and avoid legitimizing irrational responses caused by fear.Ironically, the ASTMH is the pre-eminent professional society in tropical medicine, and the annual meeting of the society is an ideal place to share scientific advances in response to EVD, an interchange that benefits both the United States and all countries facing the current epidemic. Prospective conference attendees who are actively engaged in the EVD response were prepared to share their experiences in scientific sessions, but some could not attend. Numerous attendees from west Africa, including countries not directly affected by EVD, may have been afraid to attend because of not knowing whether they would be turned away on arrival. Moreover, the DOHH reiterated their travel ban for attendees of the annual conference of the American Public Health Association held November 15–19 in New Orleans.Ebola virus causes a deadly disease, and it typically occurs in places that have underresourced and overwhelmed health systems; whereas prior outbreaks have been small and contained, the current outbreak in west Africa is of unprecedented scale.² In September of 2014, the World Health Organization declared the current Ebola virus disease (EVD) outbreak a major threat to global health and security and requested that all global health organizations and supporting countries maximize their efforts to combat the disease at its source.³ Sporadic cases in high-income countries have occurred connected to this outbreak. Because the virus is known to be transmitted by physical contact, the risk of an EVD epidemic in countries with well-equipped public health and medical systems is small. In the past, limited quarantine procedures and travel bans have been enacted for highly contagious diseases, such as Severe Acute Respiratory Syndrome (SARS). However, considering limited transmission of Ebola virus to casual contacts, there is no evidence to suggest that these strategies are needed to control EVD. On the contrary, there are detrimental consequences of inappropriately combating the outbreak in this manner. For one, health professionals who are desperately needed to combat the disease at its source are disincentivized to risk their own health.⁴ Current fear-fueled policies issued by several states in the United States are causing significant stigma toward health workers, their families, and the organizations that respond to EVD epidemics; they also marginalize people of west African descent who live in the United States and have not had any exposure to EVD.⁵ This would not be the first time that irrational reactions hampered scientific advancement and harmed patients—during the early Acquired Immune Deficiency Syndrome (AIDS) epidemic, at-risk populations were similarly marginalized.Unfounded policies, such as the Louisiana DOHH response, also have the potential to encourage potentially exposed individuals to travel outside of monitored routes, deny their exposure, and avoid diagnosis and isolation when symptomatic. Instead, the DOHH should adopt policies based on evidence, such as the established protocols of Médecins Sans Frontières and the CDC,⁶ which advise monitoring returned asymptomatic health workers. These are effective and should continue to be the basis for a response to EVD in the United States.In the case of the current EVD epidemic and other public health crises, there is a need for greater advocacy on the part of health professionals and academic and professional institutions. Beyond the responsibility of providers to care for individual patients, health professionals should raise awareness about the public health implications of inappropriate responses and policies to public health crises. The medical community should unite and attack inappropriate policies to better protect our patients and their communities. Broader advocacy at the national level and within professional societies is needed to eschew fear-induced and political decisions and maintain evidence-based, neutral, and destigmatizing responses. Such actions would serve to refocus discussion on the evidence and show solidarity on the part of health professionals with the affected population as well as the heroic providers who have chosen to combat Ebola at its source.     

From the Cover: Wireless power transfer to deep-tissue microimplants

The ability to implant electronic systems in the human body has led to many medical advances. Progress in semiconductor technology paved the way for devices at the scale of a millimeter or less (“microimplants”), but the miniaturization of the power source remains challenging. Although wireless powering has been demonstrated, energy transfer beyond superficial depths in tissue has so far been limited by large coils (at least a centimeter in diameter) unsuitable for a microimplant. Here, we show that this limitation can be overcome by a method, termed midfield powering, to create a high-energy density region deep in tissue inside of which the power-harvesting structure can be made extremely small. Unlike conventional near-field (inductively coupled) coils, for which coupling is limited by exponential field decay, a patterned metal plate is used to induce spatially confined and adaptive energy transport through propagating modes in tissue. We use this method to power a microimplant (2 mm, 70 mg) capable of closed-chest wireless control of the heart that is orders of magnitude smaller than conventional pacemakers. With exposure levels below human safety thresholds, milliwatt levels of power can be transferred to a deep-tissue (>5 cm) microimplant for both complex electronic function and physiological stimulation. The approach developed here should enable new generations of implantable systems that can be integrated into the body at minimal cost and risk.Progress in semiconductor technology has led to electronic devices that can augment or replace physiological functions; their ability to be implanted for direct interaction with organ systems relies on overall miniaturization of the device for simplified delivery (e.g., via catheter or hypodermic needle) and access to interstitial spaces. Advances over the past few decades enable most components in a biomedical device, including electrodes, oscillators, memory, and wireless communication systems, to be integrated on tiny silicon chips. However, the energy required for electronic function remains substantial and the consumption density has not been matched by existing powering technologies (1). As a result, the vast bulk of most implantable electronic devices consists of energy storage or harvesting components.Although considerable progress has been made in energy storage technologies, batteries remain a major obstacle to miniaturization (2, 3) because their lifetimes are limited and highly constrained by the available volume, requiring periodic surgical replacement once the unit is depleted. Energy-harvesting strategies have been developed to eliminate batteries or to extend their function. Previous demonstrations include thermoelectric (4), piezoelectric (5–7), biopotential (8), or glucose (9, 10) power extraction. However, these methods are anatomically specific and, in their existing forms, yield power densities too low (<0.1 μW/mm²) for a microimplant.Alternatively, energy can be transferred from an external source. Ideally, power transfer should be completely noninvasive and not specific to regions in the body. Most existing approaches for this type of transfer are based on electromagnetic coupling in the near field (11–20). Though well-suited for large devices and prostheses (21, 22), near-field methods do not address key challenges to powering a microimplant: weak coupling between extremely asymmetric source and receiver structures (23), dissipative and heterogeneous tissue (24), and regulatory power thresholds for general safety (25). These challenges, compounded by the intrinsic exponential decay of the near field, severely limit miniaturization beyond superficial depths (>1 cm), even if the battery can be removed.Theory has indicated that these problems can be overcome in the electromagnetic midfield (23): energy transfer in this region, defined to be about a wavelength’s distance from the source, occurs through the coupling between evanescent fields in air and propagating modes in tissue. Using a patterned metal plate to control the near field, we demonstrate milliwatt levels of power transfer to a miniaturized coil deep in heterogeneous tissue (>5 cm), with exposure levels below safety thresholds for humans; this enables us to power a microimplant capable of delivering controlled electrical pulses to nearly anywhere in the body. The device consists of a multiturn coil structure, rectifying circuits for AC/DC power conversion, a silicon-on-insulator integrated circuit (IC) for pulse control, and electrodes, entirely assembled within a 2-mm diameter, 3.5-mm height device small enough to fit inside a catheter. We demonstrate wireless function by operating it in human-scale heart and brain environments, and by wirelessly regulating cardiac rhythm through a chest wall.     

The associations between noise annoyance and psychological distress with blood pressure in children and adolescents: The CASPIAN‐V Study

Although blood pressure (BP) tracks from childhood to adulthood, and the prevalence of pediatric primary hypertension is increasing, related determinants are not well understood. The role of noise pollution and psychological distress in increasing BP is well documented in adults, but it remains elusive in children. This study aims to investigate the association of noise annoyance and psychological distress with BP in a pediatric population. This national cross‐sectional study was conducted in 2015 on a sample of 14400 Iranian students, aged 7‐18 years. Information regarding noise annoyance and psychological distress were assessed using questionnaires, and BP values were measured. Levels of noise annoyance and psychological distress were classified based on tertiles to no/low, moderate, and high. Data of 14274 students were completed. The mean age of participants was 12.28 (0.05), with 51% boys and 71.4% urban inhabitant. Diastolic BP and mean arterial BP (MAP) had positive correlations with noise annoyance (regression coefficient: 0.028, 95 % CI: 0.005 ‐ 0.05 and 0.025, 95 % CI: 0.002 – 0.04, respectively). Participants with higher psychological distress were 15 % more likely to experience abnormally high BP compared to those with normal psychological status or mild distresses (OR: 1.15, 95 % CI: 1.003 – 1.34). Here, we found significant positive relationships between the level of noise annoyance and values of diastolic BP and MAP. Moreover, high psychological distress showed to increase the chance of abnormally high BP. The clinical impact of these findings should be assessed in further longitudinal studies.